Methylxanthine sensitization of human colon cancer cells to Re-186-labeledmonoclonal antibody

Tumor cells lacking the functional p53 suppressor gene may arrest at the G2 phase of the cell cycle after exposure to ionizing radiation, resulting in increased radioresistance. Methylxanthines (MTXs), such as pentoxifylline (PTX) or caffeine (CAF), can inhibit the G2-phase checkpoint arrest of dama ged cells and thus radiosensitize them. However, the effect of MTX in cells irradiated with low-dose-rate p-emission is not well understood. Methods: A clonogenic assay was performed with LS180 human colon cancer cells lackin g the functional p53 suppressor gene: Cells were irradiated with increasing concentrations of Re-186-mercaptoacetyltriglycine (Re-186-MAG3)-labeled A7 monoclonal antibody against colorectal cancer (0-925 kBq/mL) at 37 degrees C in 5% CO2 for 24 h in the presence or absence of PTX (0-2 mmol/L) or CAF (0-5 mmol/L). The enhancement ratio (ER) with MTX was calculated as a ratio of 50% cell-killing concentration of Re-186-MAG3-A7 in control cells to th at in cells treated with PTX or CAF. The cell cycle distribution was analyz ed with a flow cytometer. Results: The concentration of 50% cell kill was 4 74 kBq/mL Re-186-MAG3-A7. Both PTX and CAF dose dependently enhanced the cy totoxicity of Re-186-MAG3-A7: ERs of 0.5 mmol/L PTX, 2 mmol/L PTX, 1 mmol/L CAF, and 5 mmol/L CAF were 1.50, 2.18, 1.54, and 2.63, respectively. Flow cytometry showed that the percentage nonirradiated cells in the G2/M phase of the cell cycle was 11.3% +/- 1.66%. On the other hand, cells exposed to Re-186-MAG3-A7 accumulated in the G2/M phase of the cell cycle (40.2% +/- 1 .46%), which was inhibited by the presence of 1 mmol/L PTX (19.8% +/- 8.12% ) or 2 mmol/L CAF (26.9% +/- 6.21%). Conclusion: Cellular modulation of the cell cycle with PTX and CAF radiosensitized LS180 colon cancer cells expos ed to Re-186 radiation.